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Why is RAGE called a “pattern recognition receptor”? What superpowers does it have?
RAGE (receptor for advanced glycation end products) is a 35-kilodalton transmembrane receptor that belongs to the immunoglobulin superfamily and was first described in 1992 by Neeper et al. The receptor is named for its ability to bind to advanced glycation end products (AGEs), which are glycoproteins that are nonenzymatically modified by the Maillard reaction. RAGE is often referred to as a pattern recognition receptor due to its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif.
RAGE can bind to a variety of ligands, which makes it play an important role in immune and inflammatory responses.
In addition, RAGE can bind to another agonist ligand, high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein that is essential for ribosome remodeling and can be released passively by necrotic cells or through active secretion by macrophages, natural killer cells, and dendritic cells. The interaction of RAGE with its ligands is thought to lead to the activation of pro-inflammatory genes. Because of the elevated levels of RAGE ligands in diabetes and other chronic diseases, this receptor has been hypothesized to play a pathogenic role in inflammatory diseases ranging from diabetic complications to Alzheimer's disease and even certain tumors.
Different isoforms of RAGE may have potential in providing therapeutic strategies, especially in conditions involving chronic inflammation.
Isoforms of the RAGE protein, often referred to as soluble RAGE or sRAGE, lack the transmembrane and signaling domains and may antagonize the deleterious effects of the full-length receptor, garnering much attention for the development of therapeutics for RAGE-related diseases. The RAGE gene is located in the major histocompatibility complex (MHC) III region of chromosome 6 and consists of 11 exons and 10 introns. The gene length is about 1400 stacking pairs (bp), including part of Overlapping promoter regions of the PBX2 gene.
The structural characteristics of RAGE result in two major forms: membrane-bound (mRAGE) and soluble (sRAGE). The membrane-bound form of RAGE consists of three major components: an extracellular region consisting of three immunoglobulin-like domains (including a variable V-type domain and two constant C-type domains); membrane regions, and intracellular regions that are critical for signal transduction. In contrast, soluble RAGE contains only the extracellular domain and lacks the transmembrane and intracellular domains.
The structural features of mRAGE are key to its activation of inflammatory and oxidative stress pathways, while sRAGE plays a protective role by inhibiting these pathways.
Membrane-bound RAGE (mRAGE) functions as a cellular receptor that activates inflammatory and oxidative stress pathways upon ligand binding. This allows it to be involved in various pathological conditions, such as diabetes, neurodegenerative diseases and cardiovascular diseases. Soluble RAGE (sRAGE) acts as a decoy receptor that circulates in the bloodstream and binds to RAGE ligands, thereby preventing them from activating membrane-bound RAGE. Elevated levels of sRAGE are thought to play a protective role in inflammatory diseases.
The balance between mRAGE and sRAGE levels is thought to influence disease outcome, with excess mRAGE often associated with inflammation and disease progression.
Based on its unique structure and function, RAGE has become a potential target for the treatment of chronic inflammation-related diseases. Inhibitors that prevent ligand binding to the V-domain have been investigated to reduce downstream inflammatory signaling; whereas therapies targeting the intracellular domain focus on disrupting intracellular signaling. Furthermore, increasing the levels of sRAGE may serve as an effective strategy to neutralize proinflammatory ligands and limit their interaction with mRAGE.
The diverse ligands of RAGE include AGE, HMGB1 and various S100 proteins. The interactions of these ligands trigger a series of downstream signal transduction pathways, which are important links in the development of chronic inflammatory and metabolic diseases. Will the potential and function of RAGE become the key to future medical treatment?
